Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• -workers demonstrated an enantioselective aza-Friedel–Crafts reaction between indoles 4 and isatin-derived ketimines 49. A chiral phase transfer catalyst O3 derived from urea assisted this organic transformation featuring a C3–H bond functionalization of indoles. Different protecting groups for the imine

Asymmetric tandem conjugate addition and reaction with carbocations on acylimidazole Michael acceptors

• Brigita Mudráková,
• Renata Marcia de Figueiredo,
• Jean-Marc Campagne and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 881–888, doi:10.3762/bjoc.19.65

• earlier experience, we employed the tropylium ion with the more lipophilic bis(trifluoromethane)sulfinimide (NTf2) anion because of its better solubility in the applied organic solvents than the commercially available tetrafluoroborate (BF4) form [22][23][24]. The cyclic urea DMEU (1,3-dimethyl-2

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

Preparation of β-cyclodextrin-based dimers with selectively methylated rims and their use for solubilization of tetracene

• Konstantin Lebedinskiy,
• Volodymyr Lobaz and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2022, 18, 1596–1606, doi:10.3762/bjoc.18.170

• same conditions lead to a different product in CD chemistry [30]. In the absence of strong nucleophiles such as amines, the CD gives a dimer with a urea bridge instead of providing the isocyanate. The compound 5 was synthesized from 3 according to the standard procedure [30]. The synthesis of dimers

• spectra of the dimers possess several features, making them quite different from the spectra of their starting materials. The spectra of the dimers with the urea linker in water contain much fewer distortions in the hydrogen and carbon signals than the spectra of a corresponding azido-compound, so they

• bonding. The presence of tetracene in the solution enhances inter- or intramolecular associations of CD rings in dimers. The CD dimer 5, linked with urea, demonstrated stoichiometry close to unity. Still, dimers 4 and 10, linked with triazole-based spacer, exhibited strong exothermic interaction at an

A trustworthy mechanochemical route to isocyanides

• Francesco Basoccu,
• Federico Cuccu,
• Federico Casti,
• Rita Mocci,
• Claudia Fattuoni and
• Andrea Porcheddu

Beilstein J. Org. Chem. 2022, 18, 732–737, doi:10.3762/bjoc.18.73

• reaction. This is why a solid anhydride, like the isatoic one, captured our interest, but unfortunately, the results were unsatisfying. A second idea relied on traditional coupling reagents, especially carbodiimides (DIC and DCC) [25] and CDI [26][27][28][29]. The former should generate a urea derivative

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• materials to inductively heat up glass reactors. For the Biginelli reaction solubility of the starting urea (22) as well as the products 24a and 24b were an issue being overcome by using a solvent mixture of PEG/DMF 1:1. Also the proline-catalyzed asymmetric Mannich reaction was achieved with cyclohexanone

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

• -worker have demonstrated the design and synthesis of urea-functionalized 2D/3D architectures and their catalytic activity. The urea moieties were incorporated within the building blocks and were meant to serve as binding sites for appropriate substrates, therefore, promoting selectivity and reactivity

• . For this purpose, they have chosen the ditopic bisurea “strut” 12 (Figure 3), which generated a 2D discrete molecular triangle 14 in the presence of an equimolar amount of the cis-(tmen)Pd(NO3)2 acceptor 5 [59]. In order to prevent the urea moieties on the triangle to get engaged in intermolecular H

• , which entailed the quantitative formation of the edge-directed molecular prism 15 (Figure 3). The adequate length of the ditopic clip 13 constrained the urea triangle from intersupramolecular H-bonding. Thus, the urea moieties in this newly assembled 3D architecture were freely available for

Synthesis of 5-unsubstituted dihydropyrimidinone-4-carboxylates from deep eutectic mixtures

• Sangram Gore,
• Sundarababu Baskaran and
• Burkhard König

Beilstein J. Org. Chem. 2022, 18, 331–336, doi:10.3762/bjoc.18.37

• synthesis of 5-unsubstituted dihydropyrimidinone-4-carboxylate using gem-dibromomethylarene, oxalacetic acid, and urea [25]. Here the gem-dibromomethylarene moiety serves as an aldehyde equivalent. In addition, utilizing aromatic ketones as a β-ketoester equivalent, the synthesis of 5-unsubstituted DHPM

• ] based on carbohydrates, urea, and inorganic salts as an alternative to conventional solvents for carrying out a variety of organic transformations [32]. The stable melts are environmentally friendly as they are readily available from bulk renewable resources. Their simple production allows the

• urea derivatives with β,γ-unsaturated ketoesters and subsequent intramolecular condensation could lead to 5-unsubstituted DHPM derivatives. β,γ-Unsaturated ketoester 7, derived from benzaldehyde and pyruvic acid [40], on exposure to ʟ-(+)-tartaric acid–N,N-dimethylurea (DMU) melt underwent smooth

Site-selective reactions mediated by molecular containers

• Rui Wang and
• Yang Yu

Beilstein J. Org. Chem. 2022, 18, 309–324, doi:10.3762/bjoc.18.35

• ) [60]. The host in here was a water-soluble deep cavitand D with methylated urea groups on the rim, which had already been used to mediate other organic reactions [61]. The feet of the host were transformed to pyridinium cationic moieties to make it soluble in water, and in other examples, similar

• monoamine product 47 further underwent intramolecular cyclization facilitated by the confinement of the cavitand and produced cyclized urea product 48. In a following work (Figure 13c) [78], the binding dibromide 49 showed rapid tumbling conformation in the cavity of the cavitand host E on the NMR timescale

Synthesis of a novel aminobenzene-containing hemicucurbituril and its fluorescence spectral properties with ions

• Qingkai Zeng,
• Qiumeng Long,
• Jihong Lu,
• Li Wang,
• Yuting You,
• Xiaoting Yuan,
• Qianjun Zhang,
• Qingmei Ge,
• Hang Cong and
• Mao Liu

Beilstein J. Org. Chem. 2021, 17, 2840–2847, doi:10.3762/bjoc.17.195

• heterocalixarenes, which all comprised benzimidazol-2-one and 1,3-phenylene units in an alternate cyclic arrangement. In 2008, Kwit et al. [35] synthesized urea and thiourea derivatives of chiral triangular polyimine macrocycles. The macrocycles above mainly consisted of imidazole analogs and aromatic fragments

• . Šindelář and Lizal [36] also presented the synthesis of hybrid macrocycles containing glycoluril and aromatic units. In 2014, Keinan et al. [37] reported a series of macrocycles, consisting of alternating urea or thiourea and phenol units, namely, multifarenes. Hitherto, multifarenes and their derivatives

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

• Viera Poláčková,
• Dominika Krištofíková,
• Boglárka Némethová,
• Renata Górová,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2021, 17, 2629–2641, doi:10.3762/bjoc.17.176

• aldehydes and hydrogen-bond activation of nitroalkenes. Keywords: asymmetric organocatalysis; hydrogen bond; Michael addition; pyrrolidine; thiourea; urea; Introduction Asymmetric organocatalysis became one of the strategic ways for the efficient synthesis of chiral compounds [1]. Bifunctional catalysis

• successful applications of sulfinylureas and thioureas as organocatalysts, we have designed four new N-sulfinyl-N’-(pyrrolidinylmethyl)urea and N-sulfinyl-N’-(pyrrolidinylmethyl)thiourea bifunctional organocatalysts. The main design principles are outlined in Figure 1. The catalysts feature a pyrrolidine

• unit, which should engage in enamine activation of enolizable carbonyl compounds. The urea or thiourea moiety shall provide hydrogen-bond donating ability. Furthermore, these compounds possess a sulfinyl group with an additional stereogenic center on the sulfur. To verify the influence of a matched

Adjusting the length of supramolecular polymer bottlebrushes by top-down approaches

• Tobias Klein,
• Franka V. Gruschwitz,
• Maren T. Kuchenbrod,
• Ivo Nischang,
• Stephanie Hoeppener and
• Johannes C. Brendel

Beilstein J. Org. Chem. 2021, 17, 2621–2628, doi:10.3762/bjoc.17.175

• bonding moieties are either urea-based or peptide-based (i.e., phenylalanine) units, the dodecyl chains act as hydrophobic shields to induce the amphiphilic assembly in water and prevent the surrounding water from interfering with the hydrogen bonds in the interior [29]. Attaching a hydrophilic PEO chain

Base-free enantioselective S_N2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis

• Mili Litvajova,
• Emiliano Sorrentino,
• Brendan Twamley and
• Stephen J. Connon

Beilstein J. Org. Chem. 2021, 17, 2287–2294, doi:10.3762/bjoc.17.146

• , the reactions were carried out under base-free conditions. It was found that urea-based catalysts outperformed squaramide derivatives, and that the installation of a chlorine atom adjacent to the catalyst’s quinoline moiety aided in avoiding selectivity-reducing complications related to the production

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• receptors have often proven more efficient [9][12]. A breakthrough in the field of anion binding towards its application in catalysis was achieved with the findings that neutral (thio)urea derivatives are potent anion receptors due to their ability to bind anions of various topologies, including the

• spherical halides [10]. The key to hydrogen bonding of the halide anion resides in the polarized N–H bonds of these (thio)urea units, which have since served as a benchmark in the design and development of anion receptor catalysts [12][13][14]. Consequently, other synthetic anion receptors have been

• between the catalyst and the substrate, which exclusively stabilize the transition state that forms the major enantiomer. Furthermore, Gouverneur and co-workers established an enantioselective nucleophilic fluorination protocol using a chiral bis-urea catalyst 41 and CsF as an inorganic fluoride source

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• them ideal ASO modifications as only a limited number of modifications is needed for a substantial effect. Recently, a versatile method of post-ON synthesis conjugation, different from the click chemistry method, has been applied to 2’-amino-LNA. A class of 2’-urea-LNA analogues (58–62) has been

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

• presence of strong aqueous acids (>1 M) or alkali (>1 M), is required to observe an appreciable degradation accompanied in many cases by urea or biuret as the hydrolysis products. The compounds are also relatively resistant to many classical reducing and oxidizing agents [2]. However, very strong oxidants

• such as lead tetraacetate, potassium permanganate, or refluxing hydrogen peroxide were shown to produce urea-derived degradation products [3]. Biguanides also possess a remarkable capability to form stable metal complexes, a property that was already noticed by B. Rathke in 1879 [4]. Indeed, he relied

• cyanoguanidines, dicyanamides, carbamide or N1-cyano-S-methylisothioureas and the addition of guanidines to carbodiimides, cyanamides or (iso)(thio)urea derivatives. Synthesis from amines Addition of amines to cyanoguanidines (pathway a) Reaction of amines with cyanoguanidine: The use of cyanoguanidine as the

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• construction of dihydropyrimidinones 78 utilizing a three-component reaction of acyclic 1,3-diketones 54, urea/thiourea (77) and aldehyde 5 exploring La2O3 as catalyst under microwave irradiation under solvent-free conditions with good functional group tolerance and excellent yields (Scheme 28). The reaction

Total synthesis of pyrrolo[2,3-c]quinoline alkaloid: trigonoine B

• Takashi Nishiyama,
• Erina Hamada,
• Daishi Ishii,
• Yuuto Kihara,
• Nanase Choshi,
• Natsumi Nakanishi,
• Mari Murakami,
• Kimiko Taninaka,
• Noriyuki Hatae and
• Tominari Choshi

Beilstein J. Org. Chem. 2021, 17, 730–736, doi:10.3762/bjoc.17.62

• . Consequently, we decided to develop a new synthetic strategy for the preparation of trigonoine B (1). Carbodiimides are valuable synthetic intermediates that can be obtained by an aza-Wittig reaction of isocyanates with iminophosphoranes or by dehydration of urea [26]. Molina et al. previously reported the

• -azahexatriene system. Lastly, it was proposed that the carbodiimide 10 could be derived from urea 11. Therefore, we investigated the electrocyclization of a pyrrol-3-ylbenzene containing a carbodiimide moiety. First, 2-(pyrrol-3-yl)aniline 14 was synthesized by a Suzuki–Miyaura coupling reaction of 2

• , affording aniline 15 in 65% yield. Treatment of 15 with phenyl isocyanate in CH2Cl2 gave urea 16a in 54% yield. To obtain carbodiimide 17a, 16a was treated with carbon tetrabromide (CBr4), PPh3, and Et3N in CH2Cl2. The reaction was monitored by TLC, which confirmed the complete consumption of the starting

The synthesis of chiral β-naphthyl-β-sulfanyl ketones via enantioselective sulfa-Michael reaction in the presence of a bifunctional cinchona/sulfonamide organocatalyst

• Deniz Tözendemir and
• Cihangir Tanyeli

Beilstein J. Org. Chem. 2021, 17, 494–503, doi:10.3762/bjoc.17.43

• building blocks for the construction of more elaborate structures [7][8][9][10][11]. An outstanding class of quinine derived organocatalysts exhibits a bifunctional mode of activation by the incorporation of an acidic unit, such as urea, thiourea, squaramide or sulfonamide moieties, giving rise to the

• organocatalysts 8d and 9a,b in the literature [30][41]. Among the 11 screened organocatalysts, the ones with amino-substituted DMAP cores gave unimpressive ee values (Table 1, entries 2–5). The quinine-derived organocatalysts 8a–d failed to attain striking stereoselectivity (25–43% ee). The popular urea–quinine

Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

• Alexander Leslie,
• Thomas S. Moody,
• Megan Smyth,
• Scott Wharry and
• Marcus Baumann

Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

• rearranged within a residence time of 30 minutes rendering the corresponding carbamates 3a–e in high chemical yields. Phenylacetic acid species were found to be less reactive substrates that rearranged more slowly (tRes = 60 min) and thus giving lower yields (3f–h). Moreover, the formation of urea side

• interesting case concerned the use of 3-oxocyclobutanecarboxylic acid (1m), which yielded the desired carbamate product 3m along with the carbamoyl-urea species 3m’. This observation parallels recent reports [25] proposing a fragmentation of the desired carbamate followed by a combination of the resulting

Synthesis of legonmycins A and B, C(7a)-hydroxylated bacterial pyrrolizidines

• Wilfred J. M. Lewis,
• David M. Shaw and
• Jeremy Robertson

Beilstein J. Org. Chem. 2021, 17, 334–342, doi:10.3762/bjoc.17.31

• pyrrolizidines; cyanoketones; legonmycin; vinylogous ureas; Introduction At least 40 members of the large class of pyrrolizidine alkaloids [1][2][3][4] have so far been characterized from bacterial cultures. Of these ‘bacterial pyrrolizidines’, those of the vinylogous urea type are particularly intriguing from

• various C(7a)-hydroxylated bacterial pyrrolizidines including the legonmycins, jenamidines B and C, and bohemamine D (cf. [26][27][28][29][30]). With all this in mind, we set out to develop a simplification of Snider’s route [14][15] to the vinylogous urea core for application to the synthesis of

• . The clazamycins, and selected bacterial pyrrolizidines of the vinylogous urea type. For consistency, the standard numbering convention used for the plant pyrrolizidines, as depicted for the clazamycins, is used throughout. Key species in the biosynthesis of legonmycins A (3) and B (4), and the

¹⁹F NMR as a tool in chemical biology

• Diana Gimenez,
• Aoife Phelan,
• Cormac D. Murphy and
• Steven L. Cobb

Beilstein J. Org. Chem. 2021, 17, 293–318, doi:10.3762/bjoc.17.28

• several properties of a specifically 3-FTyr-labelled α-synuclein analogue, including its native conformation and the conformational changes induced by urea, spermine and sodium dodecyl sulfate (SDS) [75]. Subsequently, α-synuclein interaction with SDS micelles and model membranes have also been

Chiral anion recognition using calix[4]arene-based ureido receptors in a 1,3-alternate conformation

• Tereza Horáčková,
• Jan Budka,
• Vaclav Eigner,
• Wen-Sheng Chung,
• Petra Cuřínová and
• Pavel Lhoták

Beilstein J. Org. Chem. 2020, 16, 2999–3007, doi:10.3762/bjoc.16.249

• recognition ability can be further strengthened by the introduction of another chiral moiety directly onto the urea N atoms. The systems with double chiral units being located around the binding ureido cavity showed better stereodiscrimination, with the highest selectivity factor being 3.33 (KL/KD) achieved

• . The shapes and geometries of anions are widely different, and therefore the design of corresponding tailor-made receptors is based mostly on more directional interactions, such as hydrogen bonds. Indeed, an incredible number of neutral receptors bearing amide, sulfonamide, urea, thiourea, pyrrole, or

• highly sophisticated molecules, including anionic receptors [27][28][29][30][31][32][33][34][35][36][37][38][39]. During our ongoing research on anion complexation, we have reported various calix[4]arene receptors based mainly on amide, urea, or thiourea groups [40][41], some of which are available in